Tao Tao, He Zhixian, Shao Zhiming, Lu Haojie
Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, P.R. China.
Department of Chemistry, Fudan University, Shanghai 200433, P.R. China.
Oncotarget. 2016 Apr 19;7(16):22807-18. doi: 10.18632/oncotarget.8182.
O-GlcNAcylation is a post-translational modification that regulates a broad range of nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes. Although previous studies have shown that increased levels of global O-GlcNAcylation and O-GlcNActransferase are linked to the incidence of metastasis in triple negative breast cancer (TNBC) patients, the molecular basis behind this is not fully understood. In this study, we have determined that the TAK1 binding protein 3 (TAB3) was O-GlcNAcylated at Ser408 by OGT in the TNBC, which was required for its Thr404 phosphorylation, TAK1 activation and downstream nuclear factor kappa B (NF-κB) activation in TNBC. O-GlcNAcylation of TAB3 was induced by p38 MAPK and it in turn enhances the TAK1 mediated p38MAPK activation, which forms the positive feedback loop in TAB3mediated NF-κB activation. In TNBC, TAB3O-GlcNAcylationmediated cell migration and invasion by activating its downstream NF-κB. The expression of TAB3 O-GlcNAcylation increased in TNBC patients, and it was significantly correlated with poor prognoses of the patients. Our study provides insights into the mechanism of TAB3 regulating activity and suggests its important implications in TNBC metastasis.
O-连接的N-乙酰葡糖胺化（O-GlcNAcylation）是一种翻译后修饰，可调节多种核蛋白和胞质蛋白，并且正逐渐成为各种生物过程的关键调节因子。尽管先前的研究表明，整体O-GlcNAcylation水平和O-GlcNAc转移酶水平的升高与三阴性乳腺癌（TNBC）患者的转移发生率相关，但其背后的分子基础尚未完全明确。在本研究中，我们确定了在TNBC中，TAK1结合蛋白3（TAB3）在Ser408位点被OGT进行了O-GlcNAcylation修饰，这是其Thr404磷酸化、TAK1激活以及TNBC中下游核因子κB（NF-κB）激活所必需的。TAB3的O-GlcNAcylation由p38丝裂原活化蛋白激酶（p38 MAPK）诱导，反过来又增强了TAK1介导的p38 MAPK激活，这在TAB3介导的NF-κB激活中形成了正反馈环。在TNBC中，TAB3的O-GlcNAcylation通过激活其下游的NF-κB介导细胞迁移和侵袭。TNBC患者中TAB3的O-GlcNAcylation表达增加，并且与患者的不良预后显著相关。我们的研究深入探讨了TAB3调节活性的机制，并表明其在TNBC转移中的重要意义。
